The immunologic consequences of HIV-1 infection are loss of T helper cell function and severe reduction of CD4+ T cell numbers. Because circulating HIV-1 consists mainly of viral particles that are not productively infectious (>99%), we investigated whether HIV-1 rendered noninfections by Aldrithiol-2 treatment (AT-2 HIV) would bind CD4+ plasmacytoid dendritic cells (pDC) and/or T cells resulting in selective apoptosis of CD4+ T cells and loss of T helper cell function. Our findings indicate that, upon 24-hr exposure to AT-2 HIV, pDC produce interferon-alpha (IFN-alpha) and indoleamine 2,3-dioxygenase (IDO). IFN-alpha is essential for inducing TNF-Related Apoptosis-Inducing Ligand (TRAIL) on CD4+ T cells, and AT-2 HIV induces TRAIL death receptor 5 (DR5) on CD4+ T cells, resulting in their apoptosis. This mechanism has been suggested to be important for eliminating HIV-infected CD4+ T cells. IDO catabolizes tryptophan, resulting in functional inhibition of CD4+ (and CD8+) T cells, which could reduce the activated target cell pool for HIV-1 infection. However, because of the higher statistical probability that HIV-CD4 binding events will be noninfectious and will kill and disarm otherwise healthy T cells, we consider that the net effect of these HIV-hijacked immune regulatory mechanisms will be immunopathogenic and advantageous for the virus. Much of our in vitro data are supported by ex vivo studies involving patient blood and lymphoid tissue.